Mechanisms of HIV-1-Specific CD4+ T Cell Dysfunction

HIV-1 特异性 CD4 T 细胞功能障碍的机制

• 批准号: 6583887
• 负责人: BRENT E PALMER
• 金额: $ 4.81万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583887
• 关键词: CD28 molecule; anergy; cell death; cell differentiation; cell proliferation; clinical research; cytokine; enzyme linked immunosorbent assay; helper T lymphocyte; human immunodeficiency virus 1; human subject; leukocyte activation disorder; postdoctoral investigator; receptor expression; virus replication

DESCRIPTION (provided by applicant): It is thought that HIV-1-specific CD4+ T cells are important for the in vivo control of HIV-1 replication in chronically infected individuals. However, the hallmark of uncontrolled, chronic HIV-1 infection is the absence of strong HIV-1-specific CD4+ T cell proliferative responses. We have shown a discordance between the frequency of cytokine producing CD4+ T cells and proliferation in the setting of unchecked HIV-1 replication. However, the mechanism behind the HIV-1-specific proliferation dysfunction remains unclear but it is mosl likely multifactorial and may involve anergy, cell death, or defects in CD4+ T cell differentiation. The hypothesis to be tested is that HIV-1 replication results in HlV-1-specific T cell anergy, activation induced ceL death (AICD), and CD4+ T cell maturational defects, all of which may contribute to the observed proliferative defect. The following specific aims will be undertaken: (1) To determine if HIV-1-specific CD4+ T cells present in subjects with active viral replication are functionally anergic, and if so, to examine the mechanisms underlying T cell hypo-responsiveness in this setting. (2) To determine if HIV-1-specific CD4+ T cells present in subjects with active replication are dying after in vitro stimulation and to determine the role that activation induced cell death (AICD) or direct cytolysis play in the loss of HIV-1-specific CD4+ T cell proliferation. (3) To examine the differentiation or maturation states of HIV-1-specific CD4+ T cells and to relate T cell maturation state to T cell functional capacity in subjects with and without active viral replication.

描述（由申请方提供）：认为HIV-1特异性CD 4 + T细胞对于慢性感染个体体内HIV-1复制的控制很重要。然而，不受控制的慢性HIV-1感染的标志是缺乏强烈的HIV-1特异性CD 4 + T细胞增殖反应。我们已经表明，在未经检查的HIV-1复制的情况下，产生细胞因子的CD 4 + T细胞的频率与增殖之间存在不一致性。然而，HIV-1特异性增殖功能障碍背后的机制仍不清楚，但它很可能是多因素的，可能涉及无反应性、细胞死亡或CD 4 + T细胞分化缺陷。待检验的假设是HIV-1复制导致HIV-1特异性T细胞无反应性、活化诱导的细胞死亡（AICD）和CD 4 + T细胞成熟缺陷，所有这些都可能导致观察到的增殖缺陷。将进行以下具体目标：（1）确定存在于具有活跃病毒复制的受试者中的HIV-1特异性CD 4 + T细胞是否在功能上无反应性，如果是，则检查这种情况下T细胞低反应性的潜在机制。 (2)确定活跃复制受试者中存在的HIV-1特异性CD 4 + T细胞是否在体外刺激后死亡，并确定活化诱导细胞死亡（AICD）或直接细胞溶解在HIV-1特异性CD 4 + T细胞增殖丧失中的作用。 (3)检测HIV-1特异性CD 4 + T细胞的分化或成熟状态，并将T细胞成熟状态与有和无活跃病毒复制的受试者的T细胞功能能力相关联。